For the first time, we have characterized mature human B cells that have an anergic phenotype, providing a critical link to twenty years of research in mice. These IgM-Low naive B cells are predominantly autoreactive and they have a reduced capacity to flux calcium, phosphorylate tyrosines or survive after stimulation. Intense stimulation causes these cells to be activated, consistent with the long-standing view that anergic B cells may be a source of pathological autoantibodies in diseases such as systemic lupus erythematosus. The long term goal of the experiments proposed herein is to translate our new basic understanding of a central mechanism of immune tolerance in humans, anergy, into a new thinking that will lead to tangible treatments of lupus. We suspect there are defects in anergic B cells that may be typical in various lupus patients, each of which could substantially alter our understanding and treatment strategies of this disease. We hypothesize that anergy is not induced or maintained for autoreactive B cells in SLE patients, allowing these cells to become fully functional. Anergic B cells may be a pool of autoreactive B cells that produce pathological autoimmune responses. To test these hypotheses in Specific aim 1, we will use flow cytometry and molecular variable gene analysis to compare the frequency and phenotype of anergic B cells in a cohort of lupus patients with age and sex matched unaffected controls.
In specific aim 2 we will determine if anergic B cells in lupus patients have altered function and the molecules involved, leading to full immune reactivity despite being autoreactive.
In specific Aim 3 we will compare the specificities and affinities of a panel of recombinant human monoclonal antibodies from anergic B cells of lupus patients to antibodies from healthy controls. With this analysis we will identify natural autoantigens that may escape tolerance and cause pathology in SLE patients.

Public Health Relevance

This study will provide an understanding of how dangerous B cells that react with our own tissues are controlled in lupus patients. The understanding of these mechanisms and exploration of how these cells are naturally controlled could provide new options for the treatment of lupus.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-QV-I)
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University of Chicago
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Kinloch, Andrew J; Kaiser, Ylva; Wolfgeher, Don et al. (2018) In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis. Front Immunol 9:1516
Chen, Yao-Qing; Wohlbold, Teddy John; Zheng, Nai-Ying et al. (2018) Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell 173:417-429.e10
Henry, Carole; Palm, Anna-Karin E; Krammer, Florian et al. (2018) From Original Antigenic Sin to the Universal Influenza Virus Vaccine. Trends Immunol 39:70-79
Wilson, Patrick C; Cobey, Sarah (2018) Characterization of the immunologic repertoire: A quick start guide. Immunol Rev 284:5-8
Stamper, Christopher T; Wilson, Patrick C (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self-Defeating Process for Eliciting Broad Protection? Cold Spring Harb Perspect Biol 10:
Leon, Paul E; Wohlbold, Teddy John; He, Wenqian et al. (2017) Generation of Escape Variants of Neutralizing Influenza Virus Monoclonal Antibodies. J Vis Exp :
He, Wenqian; Chen, Chi-Jene; Mullarkey, Caitlin E et al. (2017) Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nat Commun 8:846
DiPiazza, Anthony; Nogales, Aitor; Poulton, Nicholas et al. (2017) Pandemic 2009 H1N1 Influenza Venus reporter virus reveals broad diversity of MHC class II-positive antigen-bearing cells following infection in vivo. Sci Rep 7:10857
Lau, Denise; Lan, Linda Yu-Ling; Andrews, Sarah F et al. (2017) Low CD21 expression defines a population of recent germinal center graduates primed for plasma cell differentiation. Sci Immunol 2:
Bunker, Jeffrey J; Erickson, Steven A; Flynn, Theodore M et al. (2017) Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358:

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